TY - JOUR
T1 - A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome
AU - Genomics England Research Consortium
AU - Cuvertino, Sara
AU - Hartill, Verity
AU - Colyer, Alice
AU - Garner, Terence
AU - Nair, Nisha
AU - Al-Gazali, Lihadh
AU - Canham, Natalie
AU - Faundes, Victor
AU - Flinter, Frances
AU - Hertecant, Jozef
AU - Holder-Espinasse, Muriel
AU - Jackson, Brian
AU - Lynch, Sally Ann
AU - Nadat, Fatima
AU - Narasimhan, Vagheesh M.
AU - Peckham, Michelle
AU - Sellers, Robert
AU - Seri, Marco
AU - Montanari, Francesca
AU - Southgate, Laura
AU - Squeo, Gabriella Maria
AU - Trembath, Richard
AU - van Heel, David
AU - Venuto, Santina
AU - Weisberg, Daniel
AU - Stals, Karen
AU - Ellard, Sian
AU - Barton, Anne
AU - Kimber, Susan J.
AU - Sheridan, Eamonn
AU - Merla, Giuseppe
AU - Stevens, Adam
AU - Johnson, Colin A.
AU - Banka, Siddharth
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. Results: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition. Conclusion: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.
AB - Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. Results: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition. Conclusion: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.
KW - histone 3 lysine 4 methyltransferase
KW - intrinsically disordered region
KW - Kabuki syndrome
KW - KMT2D
KW - multiple congenital anomaly
UR - http://www.scopus.com/inward/record.url?scp=85078007652&partnerID=8YFLogxK
U2 - 10.1038/s41436-019-0743-3
DO - 10.1038/s41436-019-0743-3
M3 - Article
C2 - 31949313
AN - SCOPUS:85078007652
SN - 1098-3600
VL - 22
SP - 867
EP - 877
JO - GENETICS IN MEDICINE
JF - GENETICS IN MEDICINE
IS - 5
ER -